BOSTON - January 4, 2007 - Researchers at the Massachusetts
General Hospital (MGH) Cancer Center have discovered a novel
gene mutation associated with Wilms tumor, the most common pediatric
kidney cancer. The newly identified gene is mutated in about 30
percent of cases of Wilms tumor and is located on the sex-determining
X chromosome, which means that a single altered copy would be sufficient
for tumor formation.

"This is the first X chromosome gene directly implicated as
a tumor suppressor," says Daniel A. Haber, MD, PhD, director
of the MGH Cancer Center and senior author of the report, which
will appear in the journal Science and is receiving early
online release on the Science Express website at http://www.sciencexpress.org.
"It has the potential of someday being a useful prognostic
marker for Wilms tumor patients, and learning about its function
could tell us more about both normal kidney development and tumor
formation."

Also called nephroblastoma, Wilms tumor develops in one out of
10,000 children and is usually treated successfully with surgery
and chemotherapy. In up to 15 percent of cases, however, current
treatment protocols fail. Those with a family history of the disease
have an increased risk of developing the cancer in both kidneys
and require more complex approaches to treatment. Mutations in a
gene called WT1, first identified in 1990, cause about 5 percent
of cases, and a few other genes are associated with rare syndromes
that can include Wilms tumor.

Since so few cases of Wilms tumor could be attributed to the identified
mutations, the MGH Cancer Center researchers analyzed tumor samples
from 82 patients to search for additional genetic abnormalities.
Genome screening and sequencing tests showed that nearly 30 percent
of the samples had either deletions or mutations in the same area
of the X chromosome, indicating a new cancer gene that the researchers
have named WTX. In samples from female patients, mutated copies
of WTX were found only on the active copy of the X chromosome.

"Males have only one X chromosome, so for them a single mutation
can silence the gene and cause a tumor," Haber explains. "Females
have two X chromosomes, but one is inactivated during normal development.
We showed that mutations specifically occur on the active X in female
Wilms patients, so it takes a single genetic event to inactivate
WTX in either males or females. That's in contrast to other tumor
suppressor genes, which only can be inactivated by independent mutations
affecting both copies of the gene."

The researchers also found that WTX is expressed in cells involved
in embryonic kidney development, suggesting that it normally plays
a key role in the organ's formation. They are now investigating
the gene's normal function and studying its disruption in an animal
model.

"The biology that links pediatric cancers to normal organ development
is fascinating," says Haber. "Adult kidney cancers arise
slowly from the organ's tubules and are highly resistant to current
chemotherapy drugs, but pediatric kidney tumors arise in the early
stem cells of the kidney's filtering apparatus and are highly responsive
to chemotherapy. Following up on these findings should help us better
understand this tumor and may lead to a new appreciation of the
X chromosome's role in other forms of cancer." Haber is the
Laurel Schwartz Professor of Oncology at Harvard Medical School.

An integral part of one of the world's most distinguished medical
centers, the Massachusetts General Hospital Cancer Center is chosen
by more cancer patients than any other hospital in New England.
Known for providing individualized, compassionate care to both adults
and children, the MGH Cancer Center is comprised of 16 fully integrated,
multi-disciplinary clinical programs and a vast network of support
and educational services. Scientific investigations are conducted
as part of the largest hospital-based research program in the United
States, and a powerful synergy between physicians and laboratory
scientists fosters innovation in basic, translational and clinical
research. The MGH is consistently ranked as one of the best cancer
treatment centers in the country by US News and World Report, and
MGH nurses were the first in the state to achieve Magnet status
for exceptional nursing care.